CN113004250B - Process for preparing substituted triazole derivatives - Google Patents

Process for preparing substituted triazole derivatives Download PDF

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CN113004250B
CN113004250B CN202011508548.9A CN202011508548A CN113004250B CN 113004250 B CN113004250 B CN 113004250B CN 202011508548 A CN202011508548 A CN 202011508548A CN 113004250 B CN113004250 B CN 113004250B
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alkyl
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CN113004250A (en
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黄建
彭应龙
姜威
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present disclosure provides a process for preparing substituted triazole derivatives. Specifically, the present disclosure provides a method for preparing a substituted triazole derivative represented by formula I, which comprises the step of converting a compound of formula a and a compound of formula B into a compound of formula I under citric acid conditions. The process has the advantages of mild reaction conditions, high yield and high purity of the obtained sample, and is more suitable for the requirement of industrial mass production.

Description

Process for preparing substituted triazole derivatives
Technical Field
The disclosure belongs to the field of medicine, and particularly relates to a method for preparing a substituted triazole derivative and an intermediate thereof.
Background
In recent years, strong evidence has accumulated that oxytocin hormones play a major role in causing labor in mammals, particularly humans. By "down-regulating" oxytocin, it is expected that both direct (contractile) and indirect (increased prostaglandin synthesis) effects of oxytocin on the uterus may be blocked. Oxytocin modulators (e.g. blockers or antagonists) may be effective in treating miscarriage. There are also studies that show that preterm patients have higher oxytocin sensitivity and oxytocin receptor density than women of the same gestational age. Therefore, blocking the action of oxytocin on its receptors with oxytocin receptor antagonists is an important approach to combat preterm labor. Another condition associated with oxytocin is dysmenorrhea, which is characterized by pain and discomfort during the menstrual period. Oxytocin plays a role in the cause of dysmenorrhea due to its activity as a uterine vasoconstrictor (Akerlund et al, Ann. NY Acad. Sci.734:47-56,1994). Oxytocin antagonists may have a therapeutic effect on this condition.
WO2006077496 discloses a class of substituted triazole derivatives for oxytocin antagonists, having the following structural formula, which exhibit highly potent OTR inhibitory effect against premature ejaculation in males who have entered phase iib trial in 2017, and which show good safety and suitable pharmacokinetic profile required daily, and at the same time, there is no evidence to show inhibition or induction of CYP3a4 at 2400mg dose (see J Sex Med 2018,1-10),
Figure BDA0002845640760000011
WO2018113694 also discloses a compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2, 4-triazol-4-yl) -2-methoxypyridine, which shows a high-selectivity OTR inhibitory effect, has good brain permeability, and can effectively block the downstream function of an oxytocin receptor mediated by oxytocin, and the structural formula is as follows:
Figure BDA0002845640760000012
in view of the considerations of simplifying the preparation process and reducing the production cost, the present disclosure provides a method for preparing substituted triazole derivatives.
Disclosure of Invention
The disclosure provides a process for preparing a compound of formula I or a tautomer thereof or a pharmaceutically acceptable salt thereof,
Figure BDA0002845640760000021
the method comprises the following steps: a step of converting a compound of formula A and a compound of formula B into a compound of formula I under citric acid conditions,
Figure BDA0002845640760000022
wherein, the flow rate of the water is controlled by the control unit.
Ring A is aryl or heteroaryl, preferably C 5 -C 12 A heteroaryl group;
R 1 selected from a phenyl ring or a naphthyl ring, each independently optionallyOne or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, and heterocyclyl;
R 2 the same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, and heterocyclic group;
R 3 selected from the group consisting of alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4 selected from alkyl, preferably C 1 -C 22 Alkyl, more preferably C 6 -C 12 An alkyl group;
x is selected from a bond, O, NH or N (C) 1 -C 6 ) Preferably a bond or O;
m is 0, 1,2, 3 or 4.
In some embodiments, the compound of formula I is
Figure BDA0002845640760000023
The preparation method comprises the following steps: a step of converting the compound of formula A-1 into a compound of formula II by reacting with a compound of formula B under citric acid conditions,
Figure BDA0002845640760000024
wherein R is 1 ～R 4 X, m are as defined for compounds of formula I.
In some embodiments, the compound of formula a-1 is reacted with the compound of formula B at a temperature no greater than 100 ℃, selected from 40 ℃ to 100 ℃, and can be 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃ or any two or more between. In some embodiments, the compound of formula A-1 is reacted with the compound of formula B at a temperature of 50 to 80 ℃.
In other embodiments, R in the compound of formula I or the compound of formula II 2 Alkoxy is selected from C 1 -C 6 Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, or isomers thereof.
In other embodiments, R in the compound of formula I or the compound of formula II 1 Is selected from
Figure BDA0002845640760000031
Figure BDA0002845640760000032
Preference is given to
Figure BDA0002845640760000033
In other embodiments, the compound of formula I is
Figure BDA0002845640760000034
The preparation method comprises the following steps: a step of converting the compound of formula A-2 into a compound of formula III by reacting the compound of formula B-2 with citric acid,
Figure BDA0002845640760000035
wherein R is 1 And X is defined as in the compound shown in the formula I.
In another aspect, in some embodiments, the solvent used in the reaction of the present disclosure is selected from tetrahydrofuran.
Further, some embodiments provide methods of making charges (moles) of the compound of formula B to achieve substantially complete conversion of the compound of formula a to a limit, preferably 1:1 to 1:5, including 1:1, 1:2, 1:3, 1:4, 1:5, or any value between any two thereof.
In other embodiments, the process for preparing a compound of formula I further comprises the step of reacting a compound of formula C with a compound of formula D to form a compound of formula A,
Figure BDA0002845640760000036
wherein R is 1 、R 2 、R 4 X, m are as defined for compounds of formula A; y is selected from halogen (such as bromine and chlorine) or sulfonate group (such as OTs and OMs).
Further, the compound of formula C is reacted with the compound of formula D under basic conditions and the agent providing the basicity is selected from potassium tert-butoxide, sodium carbonate, potassium carbonate or sodium hydride. In some embodiments, the amount (molar amount) of the compound of formula D charged to achieve substantially complete conversion of the compound of formula C is preferably from 1:1 to 1:5, including 1:1, 1:2, 1:3, 1:4, 1:5, or any value between any two thereof. In other embodiments, the molar ratio of the amount (molar amount) of the agent that provides alkalinity to the amount of the compound of formula C is 1:1 to 3:1, including but not limited to 1:1, 1.5:1, 2:1, 2.5:1, 3:1, or any value between any two thereof. Further, the solvent used in this step is selected from tetrahydrofuran.
Other embodiments provide methods of preparing a compound of formula I comprising:
Figure BDA0002845640760000041
typical compounds of formula I of the present disclosure include, but are not limited to:
Figure BDA0002845640760000042
the process for preparing the compound of formula I as described in the present disclosure further comprises any step of salt formation, concentration, filtration or drying.
The compound shown in the formula I can react with acid to form salt, wherein the acid can be hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid and the like, and hydrochloric acid is preferred.
In another aspect, the present disclosure also provides a compound of formula A',
Figure BDA0002845640760000043
wherein R is 1 、R 2 X, m as defined for compounds of formula I; r is 5 Is selected from C 2 -C 22 Alkyl, preferably C 6 -C 12 Alkyl groups (including but not limited to n-hexyl, octyl, dodecyl).
In some embodiments, the compound of formula A' is provided as
Figure BDA0002845640760000044
Wherein R is 1 、R 2 、R 5 X, m are as defined for compounds of formula A'.
In still other embodiments, there is provided a compound of formula A' < CHEM > wherein
Figure BDA0002845640760000051
Wherein R is 1 、R 5 X is as defined for compounds of formula A'.
Further, other embodiments provide that the compound of formula a' is selected from:
Figure BDA0002845640760000052
wherein R is 5 As defined for compounds of formula a'.
Typical compounds of formula a' in this disclosure are selected from:
Figure BDA0002845640760000053
in another aspect, the present disclosure also provides a method of preparing a compound of formula a', comprising: a step of converting the compound of formula C 'into a compound of formula A' by reacting the compound of formula C 'with a compound of formula D',
Figure BDA0002845640760000054
wherein R is 1 、R 2 、R 5 X, m are as defined for compounds of formula A'; y is selected from halogen (such as bromine and chlorine) or sulfonate group (such as OTs).
In another aspect of the present disclosure, there is provided a method for purifying a compound of formula 2, comprising salifying a crude compound of formula 2 under acidic conditions to obtain a salt of the compound of formula 2, and then dissociating the salt of the compound of formula 2 to obtain the compound of formula 2,
Figure BDA0002845640760000061
wherein M is an acid radical.
In some embodiments, the acidic reagent used to form the salt is selected from hydrochloric acid, sulfuric acid, or phosphoric acid. The solvent used in the salt forming reaction is at least one of dichloromethane, methanol, ethanol, acetone, tetrahydrofuran or water.
In some embodiments, the agent used for liberation is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, or sodium carbonate.
In other embodiments, the solvent used for the liberation is selected from at least one of ethyl acetate, tetrahydrofuran, methanol, ethanol or water.
Further, the method for purifying the compound of formula 2 further comprises a step of crystallization of the compound of formula 2 after salification, and in some embodiments, the solvent used for crystallization is selected from ethanol/tert-butyl methyl ether.
In other embodiments, a method of purifying a compound of formula 2 comprises: salifying the crude product of the compound of formula 2 under an acidic condition to obtain a salt of the compound of formula 2, and then dissociating the salt of the compound of formula 2 to obtain the compound of formula 2, wherein an acidic reagent used for salifying is selected from hydrochloric acid, sulfuric acid or phosphoric acid, a solvent used for salifying is selected from at least one of dichloromethane, methanol, ethanol, acetone, tetrahydrofuran or water, a reagent used for dissociating is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or sodium carbonate, and a solvent used for dissociating is selected from at least one of ethyl acetate, tetrahydrofuran, methanol, ethanol or water.
The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of formula I or its tautomer, or a pharmaceutically acceptable salt thereof, prepared by the foregoing process, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The present disclosure also provides the use of a compound of formula I or a tautomer thereof or a pharmaceutically acceptable salt or pharmaceutical composition thereof, obtainable by the aforementioned process, for the manufacture of a medicament for the treatment or prevention of a disease or condition known or shown to have a beneficial effect on oxytocin inhibition, selected from sexual dysfunction, hypoactive sexual desire disorder, arousal disorder, orgasm disorder, pain during sexual intercourse disorder, premature ejaculation, pre-labour, complications of labour, appetite and eating disorders, benign prostatic hyperplasia, premature labor, dysmenorrhea, congestive heart failure, arterial hypertension, liver cirrhosis, renal hypertension, ocular hypertension, obsessive-compulsive disorder and neuropsychiatric disorders, preferably selected from sexual dysfunction, arousal disorder, orgasm disorder, pain during sexual intercourse disorder and premature ejaculation.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-octyl, n-heptyl, isooctyl, decyl, undecyl, dodecyl, various branched isomers thereof, and the like.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) m (wherein m is an integer of 0 to 2) but does not include a cyclic moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 10 ring atoms, wherein 1-4 is a heteroatom; more preferably 5 to 6 ring atoms; of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0002845640760000071
the term "aryl" refers to a 6 to 14 membered, all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0002845640760000072
aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, and heterocyclyl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0002845640760000073
Figure BDA0002845640760000081
the term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. The term "hydroxy" refers to an-OH group.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2 。
The term "cyano" refers to — CN.
The term "nitro" means-NO 2 。
The term "oxo" refers to ═ O.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
The purity or content of the compound is determined by HPLC detection, and compound characterization data is obtained by analyzing a nuclear magnetic resonance spectrum; reagents used in the present disclosure are commercially available.
Detailed Description
The present disclosure will be explained in more detail with reference to examples, which are merely illustrative of the technical solutions of the present disclosure, and the spirit and scope of the present disclosure is not limited thereto.
Example 1:
Figure BDA0002845640760000091
step 1:
adding 13.1g of compound 3(35.65mmol, prepared according to the method of example 2 in WO 2018113694) into 130ml of tetrahydrofuran, stirring for dissolving, adding 8.0g of potassium tert-butoxide in portions at 0 ℃, stirring for reacting for 30-60 min, adding 13.3g of n-dodecyl bromide (53.48mmol), stirring for reacting until the compound 3 is basically reacted completely, adding 250ml of saturated ammonium chloride solution, extracting with methyl tert-butyl ether, washing with saturated saline, drying, concentrating to obtain 22.3g of oily matter, and performing column chromatography to obtain 17.0g of oily matter, wherein the yield is: 88.9%, HPLC: 97.08 percent. MS M/z (ESI) 536.8[ M +1 ].
1 H NMR(400MHz,CDCl 3 )δ7.79(d,1H),7.75-7.70(m,2H),7.52-7.48(m,2H),7.41(d,1H),7.31-7.22(m,2H),6.66(d,1H),4.75-4.40(m,3H),4.35-4.20(m,2H),3.91(s,3H),2.85-2.50(m,2H),1.35-1.20(m,20H),0.88(t,3H)。
Step 2:
in a 500ml three-necked flask, 20g of compound 4(37.33mmol) was dissolved in 200ml of tetrahydrofuran, followed by addition of 9.70g of compound 5(93.17mmol) and 7.17g of anhydrous citric acid (37.32mmol), heating to 50-80 ℃ and stirring for reaction, after completion of the reaction, cooling, slow addition of 200ml of saturated sodium bicarbonate, extraction with MTBE, combination of the organic phases, and concentration under reduced pressure to obtain 28.9g of a solid.
Dissolving the solid in 320ml dichloromethane, dropwise adding 1N hydrochloric acid (134ml), stirring for 30min-1h, separating, drying with anhydrous sodium sulfate, concentrating to obtain 24.36g yellow sticky solid, adding anhydrous ethanol (53ml), heating, stirring to dissolve, adding MTBE (268ml), cooling to room temperature, crystallizing, filtering, washing, and drying to obtain white solid 11.25g, yield 66%, and purity 99.5%.
MS m/z(ESI):420.1[M+1]。
1 H NMR(400MHz,CD 3 OD)δ8.32(s,1H),7.75-7.84(m,3H),7.51-7.55(m,2H),7.43(d,1H),7.25-7.32(m,1H),7.00(d,1H),4.51-4.66(m,1H),4.35(t,4H),4.10(t,2H),4.00(s,3H),3.26(s,3H)。
Hydrochloride free form
The aforementioned 11.25g of white solid was added to ethyl acetate (240ml), 5% sodium carbonate (80ml, 37.74mmol) was added dropwise, stirred at room temperature, subjected to liquid separation, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 10.1g, free yield 97.6%, total yield 64%, and purity 99.6%.
Example 2
Figure BDA0002845640760000101
Step 1:
in a reaction flask, 2.0g of compound 3(5.44mmol, prepared according to the method of example 2 in WO 2018113694) is added into 20ml of tetrahydrofuran, stirred to dissolve, 1.22g of potassium tert-butoxide is added in portions at 0 ℃, stirred to react for 30-60 min, 1.58g of n-octyl bromide (8.16mmol) is added, stirred to react until the compound 3 is basically reacted completely, 45ml of saturated ammonium chloride solution is added, methyl tert-butyl ether is extracted, washed with saturated saline, dried, concentrated to obtain oily matter, column chromatography is carried out to obtain 2.41g, yield: 92.2%, HPLC: 97.9 percent.
Step 2:
in a 50ml three-necked flask, 1g of compound 6(2.08mmol) was dissolved in 10ml of tetrahydrofuran, followed by addition of 0.54g of compound 5(5.2mmol) and 0.4g of anhydrous citric acid (2.08mmol), heating to 50-80 ℃ and stirring for reaction, after completion of the reaction, cooling, slow addition of 10ml of saturated sodium bicarbonate, extraction with MTBE, and concentration of the organic phase under reduced pressure to give 1.31g of an orange solid.
Dissolving the solid in 20ml of dichloromethane, dropwise adding 1N hydrochloric acid (10ml), stirring for 30min-1h, separating, drying with anhydrous sodium sulfate, concentrating to obtain 1.08g of orange solid, adding anhydrous ethanol (2.6ml), heating, stirring for dissolving, adding MTBE (13ml), cooling to room temperature, crystallizing, filtering, washing, and drying to obtain 0.664g of white solid, wherein the yield is 69.8%, and the purity is 99.5%.
Hydrochloride free form
The above 0.664g of the white solid was added to ethyl acetate (14ml), 5% sodium carbonate (4.7ml, 2.23mmol) was added dropwise, stirred at room temperature, separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.59g, free yield 96.6%, total yield 67.4%, purity 99.4%.

Claims (4)

1. A process for preparing a compound of formula III or a tautomer thereof or a pharmaceutically acceptable salt thereof,
Figure FDA0003585282570000011
the method comprises the following steps: a step of converting the compound of formula A-2 and the compound of formula B-2 into the compound of formula III under citric acid conditions,
Figure FDA0003585282570000012
wherein the content of the first and second substances,
R 1 is selected from
Figure FDA0003585282570000013
R 4 Is selected from C 6 -C 12 An alkyl group;
x is selected from a bond or O.
2. The method of claim 1, wherein R 1 Is selected from
Figure FDA0003585282570000014
3. The method of claim 1 or 2, wherein the compound of formula III is selected from:
Figure FDA0003585282570000015
4. the process of claim 1 wherein the solvent used in the reaction is selected from the group consisting of tetrahydrofuran.
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Publication number Priority date Publication date Assignee Title
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WO2005028452A1 (en) * 2003-09-22 2005-03-31 Pfizer Limited Substituted triazole derivatives as oxytocin antagonists
WO2005082866A2 (en) * 2004-02-20 2005-09-09 Pfizer Limited Substituted 1, 2, 4- triazole derivatives as oxytocin antagonists
CN101107243A (en) * 2005-01-20 2008-01-16 辉瑞有限公司 Substituted triazole derivatives as oxytocin antagonists
WO2018113694A1 (en) * 2016-12-21 2018-06-28 江苏恒瑞医药股份有限公司 Condensed ring group azacyclobutyl triazole derivative, preparation method therefor and use thereof in medicine
CN109071492A (en) * 2016-12-28 2018-12-21 江苏恒瑞医药股份有限公司 Triazole derivative, preparation method and its application in medicine that azabicyclo base replaces

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Publication number Priority date Publication date Assignee Title
CN1429215A (en) * 2000-05-19 2003-07-09 山之内制药株式会社 Triazole derivatives
WO2005028452A1 (en) * 2003-09-22 2005-03-31 Pfizer Limited Substituted triazole derivatives as oxytocin antagonists
WO2005082866A2 (en) * 2004-02-20 2005-09-09 Pfizer Limited Substituted 1, 2, 4- triazole derivatives as oxytocin antagonists
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